Clinical StudyMelatonin Treatment Improves Insulin Resistance andPigmentation in Obese Patients with Acanthosis Nigricans

Hang Sun ,1 Xingchun Wang ,1 Jiaqi Chen ,2 Aaron M. Gusdon ,3,4 Kexiu Song,1

Liang Li,1 and Shen Qu 1

1Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University,Shanghai 200072, China2Department of Endocrinology and Metabolism, SuZhou Municipal Hospital, Nanjing Medical University, Nanjing,Jiangsu 210029, China3Division of Neuropathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA4Department of Neurology, Weill Cornell Medical College, New York, NY 10065, USA

Correspondence should be addressed to Shen Qu; qushencn@hotmail.com

Received 22 August 2017; Revised 21 December 2017; Accepted 10 January 2018; Published 12 March 2018

Academic Editor: Amelie Bonnefond

Copyright © 2018 Hang Sun et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans(AN).Methods. A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity,glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatoninwere measured. Results. After 12 weeks of treatment with melatonin (3mg/day), homeostasis model assessment insulinresistance index (HOMA-IR) (8.99± 5.10 versus 7.77± 5.21, p < 0 05) and fasting insulin (37.09 5± 20.26μU/ml versus32.10± 20.29 μU/ml, p < 0 05) were significantly decreased. Matsuda index (2.82± 1.54 versus 3.74± 2.02, p < 0 05) wassignificantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight,body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. Conclusions. Itwas concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improvinginsulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095.

1. Introduction

Melatonin is a hormone secreted by the pineal gland. Thesynthesis and secretion of melatonin are regulated by lightintensity [1]. Investigations found that melatonin hasmultiple effects and acts as an antioxidant [2, 3], has anti-inflammatory properties [4, 5], regulates circadian rhythms[6], regulates immunity [7] and has antineoplastic effects[8]. Research also found that melatonin can regulate lipidmetabolism [9], increase insulin sensitivity [10], regulateglucose metabolism [11], and reduce body weight [12].

Acanthosis nigricans (AN) is a disease characterized byskin pigmentation, hyperkeratosis, and velvet hyperplasia.Increased pigmentation commonly occurs in the posteriorneck, axilla, and groin, and it can also be seen on the cubital

fossa, labia, face, and other locations throughout the body[13]. AN can be divided into two categories: benign andmalignant [14]. Studies have found that benign AN is closelyrelated to hyperinsulinemia, insulin resistance (IR), and obe-sity [15, 16]. Many different topical and oral treatments havebeen attempted for AN. Studies reported that treatment withboth metformin and rosiglitazone are useful in AN character-ized by IR [17, 18]. Low-calorie diet, increasing physical activ-ity, and weight reduction also can relieve symptoms of AN byimproving the IR [19]. However, no safe and effective therapyexists especially when considering young patients with eugly-cemia.PatientswithANalsoareat increased riskofdevelopingmetabolic disorders such as diabetes and dyslipidemia.

Melatonin can regulate internal biological clocks andenergy metabolism [20]. Melatonin influences insulin

HindawiInternational Journal of EndocrinologyVolume 2018, Article ID 2304746, 7 pageshttps://doi.org/10.1155/2018/2304746

secretion mediated by Gi-protein-coupled melatonin recep-tors MT1 and MT2 [21]. It was found that melatonintreatment for one year could reduce fat mass and increaselean mass in postmenopausal women [22]. So this studywas designed to determine whether treatment with melato-nin is an effective treatment for AN as well as insulinresistance and metabolic disturbances.

2. Materials and Methods

2.1. Study Population. A total of 17 patients (6 males and11 females, age 27.35± 6.50) were enrolled in the 12-weekpilot open trial with no placebo group included. The studywas approved by the ethical committee of the ShanghaiTenth People’s Hospital, Tongji University, Shanghai, China,

and registered by ClinicalTrials.gov (NCT02604095). Inclu-sion criteria included (1) aging from 18 to 60 years old, (2)having acanthosis nigricans, and (3) body mass index(BMI) exceeding 28 kg/m2. Exclusion criteria included (1)malignant acanthosis nigricans; (2) serious renal, adrenal,or hepatic dysfunction; (3) taking medications chronicallyfor systemic illness; (4) lactation; (5) pregnancy; (6) activecancer; (7) taking weight-loss drugs; and (8) history of stom-ach reduction surgery. Each patient gave written informedvoluntary consent before participating in the study.

2.2. Study Design. After the initial screening, age, gender, andheight of each participant were recorded. Weight, BMI, andvisceral index were measured with light clothes and withoutshoes using an Omron HBF-358 (Q40102010L01322F,

Table 1: Effects of melatonin on various biochemical indices.

Parameters Baseline After 12 weeks of treatment p value

HOMA-IR 8.99± 5.1047 7.77± 5.2169 0.027∗

Matsuda index 2.822± 1.5423 3.744± 2.0238 0.017∗

FPG, mmol/l 5.365± 0.8645 5.341± 0.8307 0.839

Glucose 30, mmol/l 9.853± 1.9872 9.259± 1.8416 0.044∗

Glucose 60, mmol/l 10.794± 2.8203 10.247± 2.7405 0.156

Glucose 120, mmol/l 8.341± 3.1071 8.071± 3.2299 0.340

Glucose 180, mmol/l 5.835± 2.4392 5.812± 1.6605 0.939

Fasting insulin, μU/ml 37.0935± 20.26215 32.1018± 20.29752 0.010∗

Insulin 30, μU/ml 149.8935± 54.80039 116.8088± 54.59683 <0.01∗

Insulin 60, μU/ml 170.45± 83.12034 143.9794± 63.21096 0.006

Insulin 120, μU/ml 160.4506± 85.95451 135.0529± 92.32970 0.018

Insulin180, μU/ml 80.2476± 64.86455 73.1259± 67.18857 0.416

Fasting CP, ng/ml 4.8776± 1.5665 4.5759± 1.4895 0.130

TC, mmol/l 4.9312± 0.7684 4.7671± 0.7834 0.212

TG, mmol/l 1.9094± 0.7576 1.7824± 0.8641 0.338

HDL-C, mmol/l 1.1029± 0.2911 1.0741± 0.2430 0.422

LDL-C, mmol/l 3.0282± 0.6262 2.9218± 0.4897 0.221

FFA, mmol/l 0.588± 0.2233 0.506± 0.1600 0.084

UA, μmol/l 443.518± 132.5464 432.635± 111.2079 0.400

CRP, mg/l 4.6159± 3.27755 3.6429± 2.89784 0.014∗

IL-6, pg/ml 15.3318± 13.84451 13.8276± 10.09683 0.527

IL-8, pg/ml 221.1482± 321.43527 177.6976± 241.08857 0.328

TNF-α, pg/ml 28.0594± 25.81318 16.9288± 14.92093 0.040∗

SOD, U/ml 154.06± 15.262 173.35± 55.623 0.166

ALT, U/l 47.224± 23.7542 42.929± 25.7068 0.391

AST, U/l 32.400± 16.5831 30.918± 13.5636 0.625

Tbil, μmol/l 10.376± 5.3582 10.476± 5.2538 0.903

ALP, U/l 77.347± 38.9236 73.018± 37.5913 0.217

Cr, μmol/l 59.641± 14.6798 60.959± 14.6248 0.312

UN, mmol/l 4.647± 1.1906 4.924± 1.3796 0.118

fT3, pmol/l 5.1976± 0.50209 5.0829± 0.55324 0.203

fT4, pmol/l 15.3112± 1.32976 15.0959± 1.85283 0.515

TSH, pmol/l 2.75288± 1.389337 2.43759± 1.174457 0.092∗p < 0 05.

2 International Journal of Endocrinology

Japan), with the same controlling of water, food, diuretics,alcohol and coffee intake, and urination. Neck circumference(NC), waist circumference (WC), hip circumference (HC),blood pressure (BP), and heart rate (HR) were measuredtwice, and the average was used for analysis.

Scores of AN were calculated as described previously[23]. There are four degrees from 0 to 4 on the AN scales,which are strongly associated with fasting insulin and BMI.

After overnight fasting, serum glucose, insulin, C-peptide(C-p), lipid profiles, free fatty acids (FFA), uric acid (UA),inflammation factors (c-reactive protein (CRP), tumornecrosis factor alpha (TNF-α), interleukin 6 (IL-6), andinterleukin 8 (IL-8)), superoxide dismutase (SOD), alaninetransaminase (ALT), aspartate transaminase (AST), creati-nine (Cr), urea nitrogen (UN), free triiodothyronine (fT3),free thyroxine (fT4), and thyroid stimulating hormone(TSH) were measured. Participant also underwent a stan-dard 75 g oral glucose-tolerance test (OGTT) after fasting

overnight. Samples were collected at 0, 30, 60, 90, and120min, and glucose, insulin, and C-p were measured.All these measurements were performed before and after12 weeks of treatment.

Each patient received 3mg/day melatonin (SchiffNutrition Group: each tablet contains melatonin 3mg,vitamin B6 5mg, and calcium 52mg) given orally at bedtimefor 12 weeks.

2.3. Statistics and Calculations. All data were analyzed usingSPSS 21.0 software (Chicago, IL). The data are presented asthe means± SD or medians (interquartile range) for skewedvariables or proportions for categorical variables. Student’st-tests were used to compare the difference between mea-sured variables. p values< 0.05 were considered statisticallysignificant. Insulin resistance and sensitivity were assessedby the homeostasis model assessment insulin resistanceindex (HOMA-IR; fasting insulin× fasting glucose/22.5)

Table 2: Physiological measures.

Parameters Baseline After 12 weeks of treatment p value

SBP, mmHg 134.18± 10.690 131.88± 10.787 0.085

DBP, mmHg 87.53± 10.967 87.00± 11.292 0.478

HR, bmp 85.35± 7.533 82.35± 9.096 0.174

Weight, kg 100.912± 22.9884 97.453± 21.8012 0.001∗

Body fat, % 37.206± 5.3743 35.488± 6.6078 0.038∗

BMI, kg/m2 35.741± 4.7844 34.524± 4.7278 0.001∗

Visceral index 17.41± 6.510 15.82± 6.085 0.001∗

NC, cm 40.718± 4.1652 40.118± 4.1213 0.045∗

WC, cm 111.471± 13.7184 107.853± 14.2607 0.002∗

HC, cm 114.818± 10.6647 113.488± 10.5441 0.028∗

AN score, neck 3.35± 0.862 2.59± 0.712 <0.01∗

AN score, axilla 3.53± 0.717 2.65± 0.702 <0.01∗∗p < 0 05.

(a) (b)

Figure 1: Effects of melatonin on acanthosis of neck: a typical case. (a) Baseline. (b) After 12 w treatment.

3International Journal of Endocrinology

[24] and Matsuda index {1000/(Glu0× Ins0×mean-glu-cose×mean-insulin)1/2} [25].

3. Results

3.1. Insulin Resistance and Sensitivity. As shown in Table 1,melatonin treatment significantly decreased the HOMA-IR(8.99± 5.1047 versus 7.77± 5.2169, p < 0 05) and fasting insu-lin (37.0935± 20.26215 versus 32.1018± 20.29752μU/ml,p < 0 05) levels and induced the Matsuda index (2.82± 1.54

versus 3.74± 2.02, p < 0 05). There was no statistically signif-icant change in fasting glucose and fasting C peptide levels.

3.2. Physiological Measures. After 12 weeks of treatment withmelatonin, there were statistically significant changes inthe AN scores of the neck (3.35± 0.862 versus 2.59± 0.712,p < 0 01) and axilla (3.53± 0.717 versus 2.65± 0.702,p < 0 01) (Table 2). There were also significant reductionsin BMI (35.741± 4.7844 versus 34.524± 4.7278 kg/m2,p < 0 01), body weight (100.912± 22.9884 versus 97.453

Table 3: Baseline of participants.

(a)

Number Sex (1: male; 2: female) Age (year) SBP (mmHg) DBP (mmHg) HR (bpm) Height (cm) Weight (kg)

1 1 18 134 78 89 182 131.4

2 2 19 111 66 69 154 66.4

3 2 37 126 91 103 156 69

4 2 30 125 90 84 158 86.7

5 1 29 146 110 86 166 86.2

6 2 19 130 89 78 152 73.7

7 2 39 142 94 86 155.5 88.6

8 1 34 145 95 82 172 119.8

9 2 29 128 80 89 160 93.9

10 1 28 120 90 89 182 127.6

11 2 24 132 86 92 174 100.2

12 2 25 138 86 78 167 121

13 2 28 135 79 86 165 93.8

14 2 35 136 78 87 160 99.1

15 2 22 149 94 94 178 104.6

16 1 18 132 76 83 175 103.5

17 1 31 152 106 89 183 150

(b)

Number Fat (%) BMI (kg/m2) Visceral index NC (cm) WC (cm) HC (cm) AN score, neck AN score, axilla

1 35.5 39.7 24 45.5 120.5 131.2 4 4

2 30.5 28 8 36 90.3 99.5 4 4

3 34.4 28.4 9 39.7 98 96 3 2

4 38.7 34.7 16 42 106.5 119.2 4 4

5 25 31.3 16 41.5 100.2 105 4 4

6 34.2 31.9 10 38.5 98.5 103 4 4

7 42.5 36.6 21 38 110 117 4 4

8 37.7 40.5 30 48.5 130 121 4 4

9 41.9 36.7 19 39 115 109 2 3

10 34.4 38.5 25 45 129 116 4 4

11 40.7 33.1 13 37 108 118 4 4

12 43.6 43.4 27 36 108 132 4 4

13 41 34.5 15 43 105 120 2 2

14 43.2 38.7 22 41.5 115 104 3 3

15 38.9 33 12 35 105 116 3 4

16 29.1 33.8 14 38 110 117 2 3

17 41.2 44.8 15 48 146 128 2 3

4 International Journal of Endocrinology

± 21.8012 kg, p < 0 01), body fat (37.206± 5.3743% versus35.488± 6.6078%, p < 0 05), and visceral index (17.41± 6.510 versus 15.82± 6.085, p < 0 01) (Table 2). Pigmenta-tion in patients with AN was improved after treatment(Figure 1). Melatonin also decreased NC (40.718± 4.1652versus 40.118± 4.1213 cm, p < 0 05), WC (111.471± 13.7184versus 107.853± 14.2607 cm, p < 0 01), and HC (114.818± 10.6647 versus 113.488± 10.5441 cm, p < 0 05) (Table 2).

3.3. Lipid and Inflammatory Parameters. As shown inTable 1, there were no significant decreases in serum lipids(TC, TG, LDL-C, and HDL-C). CRP (4.6159± 3.27755 versus3.6429± 2.89784mg/l, p < 0 05) and TNF-α (28.0594± 25.81318 versus 16.9288± 14.92093, p < 0 05) weredecreased significantly, but IL-6 and IL-8 did not decreasesignificantly. There were also no changes in serum SOD,ALT, AST, Cr, UN, fT3, fT4, and TSH (Table 2). The baselineof participants is showed in Table 3.

4. Discussion

In 2000, AN was established as a formal risk factor for thedevelopment of diabetes in children by the American Diabe-tes Association [16]. Insulin resistance commonly occurs inassociation with AN.

The cutaneousmanifestations of AN are caused by hyper-insulinemia and the stimulation of keratinocytes and dermalfibroblasts by growth factors [26, 27]. Patients with hyperin-sulinemia have increased IGF-1 levels [28]. Hyperinsulinemiais able to reduce IGF binding protein- (IGFBP-) 1 andIGFBP-2, which regulate levels of IGFs. Reduced IGFBP-1and IGFBP-2 levels could increase free IGF-1, therebypromoting the development of papillomatosis and hyperker-atosis observed in AN [29]. There are two membrane recep-tors of melatonin called MT1 and MT2, which are G-protein-coupled receptors, in the periphery [30]. Bothreceptors are expressed in the islets of Langerhans and areinvolved in the regulation of glucagon secretion from α-cellsand insulin secretion from β-cells [10]. Numerous studiessupport that activation of MT1 or MT2 leads to a reductionin second messenger 3′,5′-cyclic adenosine monophosphate(cAMP) or 3′,5′-cyclic guano-sine monophosphate (cGMP)accompanied by reduced insulin secretion [31, 32]. Picinatoet al. [33] found the effects of melatonin on the phosphor-ylation of IGF and insulin receptors triggering theirsignalization cascade. Therefore, the effect of melatoninon insulin secretion and IGF may explain the mechanismof action behind the utility of treating AN with melatonin.

Most patients with AN also have severe obesity. Accumu-lating evidence shows that obesity is a clinical indicator forthe risk of cardiovascular diseases, diabetes mellitus, andthe associated metabolic syndrome [34, 35]. Somewhatsurprisingly, we found that treatment with melatonin foronly 12 weeks significantly decreased body weight, BMI,body fat, and visceral index of obese participants. Previousstudies have shown that NC is associated with the metabolicdisorders related to insulin resistance, cardiovascular dis-eases, metabolic syndrome, and obstructive sleep apneasyndrome [36, 37]. Melatonin was also found to decrease

NC and WC, which are commonly considered as risk factorsfor metabolic syndrome.

Numerous studies have demonstrated that melatonin hasantioxidant [2, 3] and anti-inflammatory [4] functions. Inour study, serum CRP and TNF-α were decreased. Someinvestigators have suggested that the inflammation inducedby metabolic surplus is different from classical inflammation[38]. TNF-α was the first inflammatory marker discovered inadipose tissue of obese mice [39]. As another inflammatorymarker, CRP has been shown to be associated with anincreased risk for development of type 2 diabetes mellitus(T2DM) [40]. We consider the anti-inflammatory functionof melatonin as one of the possible mechanisms by which itimproves AN.

This study had several limitations. Firstly, recruitment todiabetes trials has long been associated with placebo-mediated improvements in glycemic control and associatedmetabolic parameters [41]. But because of the lack resourcesto perform additional placebo arm studies, we do not haveenough ability to recruit placebo-controlled subjects. Sec-ondly, the sample size of the present study was relativelysmall. Because of the individual difference, we could not seesignificant changes in lipid metabolism and antioxidationfunctions. Secondly, we could not measure the overnighturinary 6-sulfatoxymelatonin excretion (UME), which canreflect the level of internal melatonin, of the outpatients.Further studies are necessary to prove these conclusions.

5. Conclusion

In summary, treatment with melatonin can decrease weight,adipose tissues, and cutaneous symptoms in obese patientswith AN. It may act through improvement of insulin resis-tance and decreasing inflammation. However, further workmust be done to elucidate its complete mechanism of action.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Hang Sun, Xingchun Wang, and Jiaqi Chen contributedequally to this work.

Acknowledgments

The present study would not have been possible without theparticipation of the patients. The abstract of this research hasbeen published in ADA in 2016. This study is supported bythe Program for Outstanding Medical Academic Leader,Central University Cross Fund, and Chinese Medical Associ-ation Fund (nos. 12020550355 and 22120170145).

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